Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.

Autor:	Boddu PC; Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 786, New Haven, CT 06511, USA., Gupta AK; Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 786, New Haven, CT 06511, USA., Roy R; Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 786, New Haven, CT 06511, USA., De La Peña Avalos B; Department of Biochemistry and Structural Biology, University of Texas Health Science Center (UTHSC) at San Antonio, San Antonio, TX, USA., Olazabal-Herrero A; Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 786, New Haven, CT 06511, USA., Neuenkirchen N; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA., Zimmer JT; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Chandhok NS; Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA., King D; Section of Hematology and Medical Oncology, Department of Internal Medicine and Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI, USA., Nannya Y; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan., Ogawa S; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan., Lin H; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA., Simon MD; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Dray E; Department of Biochemistry and Structural Biology, University of Texas Health Science Center (UTHSC) at San Antonio, San Antonio, TX, USA., Kupfer GM; Department of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA., Verma A; Division of Hemato-Oncology, Department of Medicine and Department of Developmental and Molecular Biology, Albert Einstein-Montefiore Cancer Center, New York, USA., Neugebauer KM; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University, New Haven, CT, USA., Pillai MM; Section of Hematology, Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 786, New Haven, CT 06511, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: manoj.pillai@yale.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Apr 18; Vol. 84 (8), pp. 1475-1495.e18. Date of Electronic Publication: 2024 Mar 22.
DOI:	10.1016/j.molcel.2024.02.032
Abstrakt:	Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy. Competing Interests: Declaration of interests Amit Verma has received research funding from Prelude, B.M.S., G.S.K., Incyte, Medpacto, Curis, and Eli Lilly; is a scientific advisor for Stelexis, Bakx, Novartis, Acceleron, and Celgene; receives honoraria from Stelexis and Janssen; and holds equity in Stelexis and Bakx. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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